S-niteo-z-fubftjewdene



United States ate nt H 3,001,992 NEW SERIES OF N-(S-NITRO-Z-FURFURYLIDEND- AMINOHETEROCYCLES Elizabeth A. Bellamy, Belleville, NJ., and Kenyon J. Hayes and Julian G. Michele, Norwich, N.Y., assignors to The Norwich Pharmacal Company, Norwich, N.Y.,

a corporation of New York No Drawing. Filed Nov. 17, 1958, Ser. No. 774,112 6 Claims. (Cl. 260-240) This invention relates to a new series of chemical compounds which have exhibited a high order of in vivo chemotherapeutic effectiveness against microbial infections upon oral administration. The series includes a number of closely related N-(S-nitro-2-furfurylidene)- aminoheterocycles which may be represented by the wherein Z represent the atoms which are necessary to complete a six membered heterocyclic ring selected from the group consisting of 2-piperidone, hydrouracil, tetrahydro-2(l)-pyrimidone, morpholine, piperidine and 4- methyl piperazine. 1

We have discovered that the members of our new series of compounds are potent and valuable chemotherapeutic agents in the treatment of subjects infected with a variety of pathogenic microorganisms. Our compounds administered orally to animals infected with Salmonella typhosa, Micrococcus pyogenes var. aureus, Syphacia obvelata or Eimeria tenella organisms'have proved successful in ameliorating-and preventing morbidity and mortality provoked by such organisms. Our new compounds have exhibited the further surprising property of combatting Trichomonas vaginalis effectively when administered per os.

The amount of our compounds necessary to effect a therapeutic result is well tolerated without manifestation of toxic or undesirable response. When fed to mice infected with Salmonella typhosa, Microcaccus pyogenes var. aureus, Syphacia obvelato or Trichomonas vaginalis organisms at a dose within the range of 50-250 mg./kg. cures obtained, in percent, were 80, 100, 90, and 90, respectively. When incorporated in the feed supply of chickens exposed to infection by Eimeria tenella at the low level of 0.011%, protection against the ravages of coccidiosis produced by that parasite was secured.

In mice the LD of our compounds is within the range of 400-2200 mg./kg. In chickens adverse effects due to the. presence of our compounds in their feed have not been observed.

ceutical practice are employed. They are also readily used in the treatment of diseases of domestic animals by incorporation in the feed supply and thus are peculiarl valuable in the field of veterinary medicine.

The method which we now prefer to follow in preparing the members of our new series comprises con- (lensing the appropriate N-aminoheterocycle withS-nitro- Z-furfural or a derivative thereof capable of yielding that 3,001,992 Patented Sept. 26, 1961- EXAMPLE I N- -m'tro-2-furfurylidene) -3-amin0tetrahydro-2 (1 pyrimidone E O,NU-CH=N-N NH Hg H5 1. c

A solution of 7.0 g. (0.07 mole) of tetrahydro-2(1)- pyrimidone in 200 cc. of 2 N sulfuric acid is cooled at 3-4 C. 'while 4.9g. (0.071 mole) of solid sodium nitrate are added during .6 minutes. Stirring is continued for about 5. hours. During 10 minutes, 10 g. (0.153 mole) of zinc dust are added at l5-20 C. Stirring is continued for minutes; then the excess zinc is filtered. A solution of 10 g. of S-nitro-Z-furfural dissolved in ethanol'is added 25 and the yellow precipitate which forms is removed by filtration. After washing with water, alcohol, ether and drying, the product weighs 12.1 g. (73%) and melts at 238-245 C. Recrystallization from nitromethane raises the melting point to 242.5-244.5 C. "Instead of S-nitro-Z-furfural, 5-nitro2-furaldehyde diacetate may be used. When it is employed, heat is supplied to the mixture to raise the temperature to about 75-85 C. for a brief time to effect its hydrolysis.

. EXAMPLE II 1y-(.i-nirroQ-furfurylidene)-1-amino-2-piperidone (3 DIN I olCH=NlTI CHs A solution of 65 g. (0.657 mole) of Z-piperidone'in 250 cc. of glacial acetic acid is cooled in ice whiledried nitrous gases (generated from sodium nitrite and sulfuric acid) are passed in until saturated'(about 12 hours). The resulting solution is placed under vacuum to remove excess nitrogen oxides and then poured onto ice. Zinc dust is added in small portions until the yellow color disappears. Stirring is continued for an additional hour. The excess zinc is filtered and the aqueous solution treated with 25 g. of 5-nitro-2-furfural dissolved in ethanol. The yield of product, melting at 232-233 C., is 17 g. (11%).

Recrystallization from 1:1 nitromethanezethanol raises.

I EXAMPLE III N (5 -n itro-Z-furfury lidene) -am inohydrouracil.

Hz /C=O C (A) l-AMINOHYDROURACIL HYDROCHLORIDE A solution of 7 g. (0.0476 mole) of Z-semicarbazido- 70 propionic acid dissolved in 39 g. of 25% hydrochloric acid is heated at 75-80 C. for 45 minutes. The reaction mixture is cooled below 10 C. for 30 minutes after the melting point to arninohydrouracil hydrochloride, obtained in A, is added a solution of 0.85 g. of 5-nitro-2-furfural dissolved in ethanol. The yellow precipitate which forms is filtered and washed with alcohol and ether, giving 1.3 g. (86.6%) of N-(5-nitro-2-furfurylidene)-1 aminohydrouracil. After recrystallization from dimethylformamide it melts at 280 C.

EXAMPLE IV N-(5-11itro-Z-furfurylidene)el -amirtga4-methyl piperazine M? 'N- Q Q' METEYP REPEEEQINP In a s on f s mole at imet y p pe oz ipe in 2000m1. of 2 N sulfuric acid is added a solut n o 0 a- -3 l s) f s dium ni r te di solve in 300 ml. of water during two hours at 5 5 0 After a addi i n 1/2 o the o t o is sool t To i solution is added 400 ml. of 20% sodium hydroxide to bring the pH to about 8.4. The solution is extracted ten times with 100 ml. portions of chloroform. After drying and removing the (chloroform in vacuo, the residue is dis ill d hr u h a iew; Qlumn- Ih y e d Qf ye low1iquid boiling at 76 C. (1.5 is 151g, (S -5% (B) N- (5-NITRO-2-FURFUBX1QIDENE)-1-AMINO-4- METHYL PIPERAZINE In a 5 l. flask equipped with a stirrer, a reflux condenser with drying tube, a thermometer, and a dropping funnel are placed 45 g. (1.2 moles) of lithium aluminum hydride. Anhydrous ether 1,209 ml.) is added and the suspension stirred and refluxed for one'hour.

After cooling to 5 C. a solution of 110 g. (0.85 mole) of N-nitroso-4-methyl piperazine in 500 ml. of anhydrous ether is added at such a rate that the temperature does not exceed C. After stirring an additional hour, 300 ml. of ether are added slowly and then 125 ml. of water are added dropwise at 6- 22 C. during ;20 minutes. The white solid is filtered, collected, and washed by (slurry- .ing with ether. The ether is evaporated and the resid treated with 400 ml. of water. After the addition of 10 ml. of acetic acid, the pH is 4:5,. ASQllltiQn of 120 g. (0.85 vmole) of 5-nitro-2 fur u. .l in 250 of ethanol is added at 45 C. After standing one hour, thesolution is extracted with ether two times. Then, 2110 ml, of sodium carbonate solution (100g. monohydrate in 200 N 5 -nitro- 2-furfurylidn) -aminor1iarpholine dNlCLaN es (A) N-NrrnosotronPHomNn In a l l. flask fitted with a stirrer, thermometer, and reflux condenser are placed 87 g. (1 mole) of morpholine and 550 ml. of 2 N sulfuric acid. The solution is heated on the steam bath to 60 C. and a solution of 79 g. (1.15 moles) of sodium nitritein ml. of water is added during two hours at 60-65 C., after which the heating is continued for one hour.

(B) N.-(ErNITROFZ-FURFURYLIDENE)4 3M910- MORPHOLINE The cooled nitrosation mixture is added to 3500 ml. of 2 N sulfuric acid in a 12 l. flask equipped with a stirrer and a thermometer. Then g. (2.37 moles) of zinc dust are added portionwise to the stirred solution at such a rate as to keep the temperature below 20 C. addition requires about one hour. After stirring an additional thirty minutes, the excess zinc is filtered. Then 141 g. (1.0 mole) of 5.-nitr o furfural are dissolved in one liter of ethanol, and one-third of this is added to the amine solution at 40 C. After crystallization begins, the remainder of the solution is added and the mixture stirred one-half hour at 45 C., then cooled to 5l0 C. for two hours, filtered, and washed with water. The crystals are dissolved in 2500 ml. of hot isopropanol. To the hot solution are added about 10 g. of decolorizing charcoal. After stirring briefly, the mixture is filtered and washed with 5.00 ml. of hot isopropanol. The orange crystals obtained are dried. The yield of N-(5-nitro-2-furfurylidene)-aminomorpholine is 172 g. (76.5%); M.P. 119- 120 C.

XAM L W N 5-nitra-2sfurfuryliafeneplraminopiperiding (YA) ,N-NITROSOPIPERIDINE To a solution of 198 ml. (170 g, 2 moles) of piperidine in 1000 ml. of 2 N sulfuric acid is added a solution of g. (2.32 moles) of sodium nitrite in 300 ml. of water during two or three hours at'55-65 C. The pH gradually rises during the reaction from an initial pH of 3.1 to a pH of 5.0 after most of the nitrite has been added. Two

5 ml. portions of 2 N sulfuric acid are added towards the end of the reaction to maintain the pH below 5. 'After the nitrite addition is complete, the solution is stirred an additional hour at 50-60 C. The cooled solutionis extracted three times with 100 ml. portions of chloroform. The chloroform solution is dried, the chloroform removed, and the residue distilled in vacuo. There are obtained 209 g. (92% yield) of nitrosopiperidine, boiling at 61 C. (at 1 mm.) to.67 C. (at 1.5 mm).

(B) N- s-mmoanonnunrmnnnn -1-AMIN0- PIPERIDINE In a 12 l. flask fitted with a stirrer and thermometer are placed 134g. (1.615 moles) of nitrosopiperidine and 5800 ml. of 2 N sulfuric acid. The solution is cooled to 15 -C. in an ice-water bath. Then 250 g. (3.82 moles) of zinc dust are added portionwise with stirring, at such a rate as to keep the temperature below 20 C. This requires about one and one-half hours. The excess zinc dust is filtered. To the filtrate'are added 1500 ml. of ethanol. A solution of 240 g. (1.70 moles) of 5-nitr0-2- furfural in 1750 ml. of ethanol is added. The mixture is stirred for about one-half hour at room temperature and then cooled two to three hours in an ice-bath. The orange needles are filtered and washed well with water. After air-drying and drying-two hours at 60 C., the yieldof 6 N-(S-nitro-Z-furfurylidene) -1-aminopiperidine is 281 g. 5. N-(5-nitro-2-fu-rfurylidene)-1-aminomorpholine. (77.4%); MP. 8990.5 C. 6. N-(5-nitro-2-furfurylidene)-l-aminopiperidine.

What is claimed is: 1. The compounds having chemotherapeutic activity on eferences Cited in the file of this patent oral administration of the formula: 5 UNITED STATES PATENTS 1 2,702,292 Hayes Feb. 15, 1955 l L 2,746,960 Gever et al May 22, 1956 ON 0 I 2,798,068 Gever July 2, 1957 in which Z represents the atoms which are necessary to 10 FOREIGN PATENTS complete a six-membered heterocyclic ring selected from 759,378 Great Britain Oct. 17, 1956 the group consisting of Z-piperidone, hydrouracil, tetra- 1,063,601 Germany Aug. 20, 1959 hydro-2(1)-pyrimidone, morpholine, piperidine and 4- OTHER REFERENCES methyl piperazine. n

2 N (5 it 2 f f 1id 3 i t h d 2(1) 15 R1ch-ter: Organic Chemistry, volume I11, pages 3 to 5, pyrimidone. P. Blakistons Sons & C0., 1923.

3. N (S-nitro-Z-furfurylidene)-1-amino-2-piperidone. Derwent Belgian Patents Report, VOL 63A, P A23 4. N-(S-nitro-Z-furfurylidene)-1-aminohydrouracil. (Mar- 1960)- 

1. THE COMPOUNDS HAVING CHEMOTHERAPEUTIC ACTIVITY ON ORAL ADMINISTRATION OF THE FORMULA: 